Are Human Leukocyte Antigens (HLAs) the genes that determine which antigens the immune system detects?

Human Leukocyte Antigens (HLAs) and Antigen Detection by the Immune System

Yes, HLA genes determine which antigens the immune system can detect and present to T cells, playing a central role in immune recognition and response. 1

Role of HLA in Antigen Recognition

HLA genes encode proteins that form complexes that present antigenic peptides to T cells, influencing both thymic selection and T-cell activation 1. These genes are located on chromosome 6 and are divided into three main classes:

• MHC Class I molecules (HLA-A, HLA-B, HLA-C):

  • Expressed on nearly all nucleated cells
  • Present self-proteins or cytosolic pathogens to CD8+ T cells
  • Consist of an α-chain (encoded in MHC class I region) and β2-microglobulin (chromosome 15)
  • Binding groove is closed at both ends, restricting peptide size 1, 2

• MHC Class II molecules (HLA-DP, HLA-DQ, HLA-DR):

  • Expressed primarily on antigen-presenting cells
  • Present processed extracellular pathogens to CD4+ T cells
  • Consist of α and β chains (both encoded within MHC)
  • Binding groove is open-ended, accommodating peptides of variable length 1, 2

• MHC Class III region:

  • Contains additional genes involved in immune and inflammatory responses (e.g., complement genes) 1

Antigen Processing and Presentation Pathways

The HLA system facilitates two main pathways for antigen presentation:

1. Endogenous pathway (Class I):

   • Processes intracellular proteins via proteasomes
   • Peptides are translocated from cytosol into endoplasmic reticulum
   • HLA class I complexes form and transport to cell surface 2

2. Exogenous pathway (Class II):

   • Processes antigens that enter the cell via pinocytosis or receptor-mediated internalization
   • "Invariant chain" protects the groove from binding peptides in the ER
   • In endosomal compartment, invariant chain degrades and antigenic peptides bind to HLA class II 2

Functional Significance of HLA Diversity

HLA genes are the most polymorphic loci in the human genome 3. This diversity has important functional implications:

• Each HLA variant has its own repertoire of presented peptides with specific sequence motifs 3
• Different HLA variants show preferences for presenting proteins with specific molecular functions
• Some HLA variants preferentially present membrane and receptor proteins, while others present ribosomal and DNA-binding proteins 3
• This diversity allows for broader immune surveillance and pathogen recognition

Clinical Relevance

The HLA system's role in determining antigen recognition has significant clinical implications:

• Autoimmune diseases: Specific HLA alleles are strongly associated with autoimmune conditions like type 1 diabetes 4
• Transplantation: HLA mismatches can trigger alloreactivity and rejection 2
• Infectious disease susceptibility: Different HLA variants show differential ability to present viral proteins from pathogens like HIV, influenza, and SARS-CoV-2 3
• Cancer immunotherapy: HLA evolutionary divergence may affect response to immunotherapy 1

Evolutionary Advantage

HLA diversity provides evolutionary advantages:

• HLA alleles inherited in haplotypes often have complementary presentation preferences
• Frequent haplotypes in human populations tend to include HLA variants that present diverse sets of peptides
• This complementarity helps avoid "holes" in the immunopeptidome 3
• The concept of "divergent allele advantage" suggests that carrying two divergent HLA alleles allows presentation of a wider range of antigens 1

In summary, HLA genes are indeed the genetic determinants that enable the immune system to detect and respond to specific antigens, forming the foundation of adaptive immunity and influencing susceptibility to various diseases.